Cycloaddition regiochemistry

AMI calculations were performed using SPARTAN software, and these FMO predictions are consistent with the fact that the observed cycloaddition regiochemistry is generally /t -FMO . The HOMO/LUMO energies are listed in Table 9, and Figure 10 depicts the coefficients for the favored HOMO(miinchnone) - - LUMO(nitroindole) interaction (HOMO = highest, occupied molecular orbital LUMO = lowest unoccupied molecular orbital). 

Exceptions do exist, however, and one must be particularly alert to substituent-induced changes in the direction of polarization, as well as to their affect upon the energy of the frontier molecular orbitals. For example, nitrone cycloaddition regiochemistry is generally LU controlled, leading to the production of C-S substituted isoxazolines in excellent yield. However, as the ionization potential of the nitrone decreases or the electron affinity of the dipolarophile increases, there exists an increased propensity for formation of the C-4 regioisomer. Eventually, a switch from LU to HO control occurs and substantial amounts of the C-4 isomer are produced (equation 14). 

The rationalization of the regiochemistry is given in Eq. 16.35. It is convenient to think of the T] state of the enone as being polarized in the manner shown. If we consider the excited state to have biradical character, a radical next to a carbonyl should be relatively electrophilic. When a polarized olefin approaches, the product arises by connecting the nucleophilic end of the olefin to the electrophilic carbon a to the carbonyl. Whether this is a mechanistic insight or a useful mnemonic, it does allow the prediction of cycloaddition regiochemistry in many, but not all, cases. 

When both the 1,3-dipoIe and the dipolarophile are unsymmetrical, there are two possible orientations for addition. Both steric and electronic factors play a role in determining the regioselectivity of the addition. The most generally satisfactory interpretation of the regiochemistry of dipolar cycloadditions is based on frontier orbital concepts. As with the Diels-Alder reaction, the most favorable orientation is that which involves complementary interaction between the frontier orbitals of the 1,3-dipole and the dipolarophile. Although most dipolar cycloadditions are of the type in which the LUMO of the dipolarophile interacts with the HOMO of the 1,3-dipole, there are a significant number of systems in which the relationship is reversed. There are also some in which the two possible HOMO-LUMO interactions are of comparable magnitude. 

Lastly, perfluoropropyne undergoes cycloaddition with diphenyldia-zomethane to give a single product, although the regiochemistry is undetermined... 

Because the fluorine substituents both inductively and hyperconjugatively withdraw electron density from the C(2)-C(3) tt bond, the LUMO is located there, and Diels-Alder reactions take place exclusively with this bond [25] 1,1 -Difluoro allene and fluoroallene reaet readily with a large selection of cyclic and acyclic dienes, and acyclic dienes, [2+2] cycloadditions compete with the Diels-Alder processes As shown in the example in equation 79, a significantly different regiochemistry is observed for the [2+4] cycloaddition compared with the [2+2]... 

Bis(tnfluoromethyl)-4,5-dihydrooxazin-6-ones [28] and their O-acetylated dcnvatives [96] are formed on treatment of acyl imines with acetyl chloride-hiethylamine at room temperature. The reaction was interpreted as a cycloaddition reaction involving a ketene [28] However, the periselectivity and regiochemistry of this reactwn-are not in agreement with results obtained from the reaction of... 

The A-benzenesulfonyl imines of hexafluoroacetone readily react with nitrile oxides to give [3-1-2] adducts, apparently in a multistep reaction [151] (equation 36) Although only a few examples of [3-1-2] cycloaddition reactions of this type have been descnbed so far, most 1,3-dipoles should react in this way with predictable regiochemistry [5 146, ISO 151]... 

In contrast, when ot,P-unsaturated multiple bond systems act as dienophiles in concerted [4+2] cycloaddition reactions, they react across the C=C double bond Periselectivity as well as regiochemistry are explained on the basis of the size of the orbital coefficients and the resonance integrals [25S]... 

Early work established that S4N4 forms di-adducts with alkenes such as norbornene or norbomadiene. Subsequently, structural and spectroscopic studies established that cycloaddition occurs in a 1,3-S,S"-fashion. The regiochemistry of addition can be rationalized in frontier orbital terms the interaction of the alkene HOMO with the low-lying LUMO of S4N4 exerts kinetic control. Consistently, only electron-rich alkenes add to S4N4. 

An interpretation based on frontier molecular orbital theory of the regiochemistry of Diels Alder and 1,3-dipolar cycloaddition reactions of the triazepine 3 is available.343 2,4,6-Trimethyl-benzonitrile oxide, for example, yields initially the adduct 6.344... 

The description of the regiochemistry of the cycloaddition products of dienes that have two or more dissimilar substituents may require incorporation of their name in the new notation (Equations 1.18 [38] and 1.19 [39]). 

The ortho-para rule is explained by FMO theory on the basis of the orbital coefficients of the atoms forming the cr-bonds. The regiochemistry is determined by the overlap of the orbitals that have larger coefficients (larger lobes in Scheme 1.15). The greater the difference between the orbital coefficients of the two end atoms of diene and two atoms of dienophile, which form the two cr-bonds, the more regioselective the cycloaddition. 

Diels-Alder reaction of the furan derivative 148 with homochiral bicyclic enone 149 is the key step [56] in the total synthesis of the diterpenes jatropho-lone A and B, 151 and 152, respectively, isolated from Jatropha gossypiifolia L [57], Initial efforts to carry out the cycloaddition between 148 and 149 under thermal or Lewis-acid conditions failed due to diene instability. Application of 5kbar of pressure to a neat 1 1 mixture of diene and dienophile afforded crystalline 150 with the desired regiochemistry (Scheme 5.23). Subsequent aromatization, introduction of the methylene group, oxidation and methylation afforded (-l-)-jatropholones 151 and 152. 

The aqueous aza-Diels-Alder reaction of an aldehyde and an amine hydrochloride with a diene is catalyzed by lanthanide(III) trifluoromethane sulfonates (Ln(OTf)3, triflates [24]). Some examples are reported in Schemes 6.12 and 6.13. With respect to uncatalyzed reactions, the lanthanide catalyst allows milder reaction conditions, increases the reaction yield and does not affect the diaster-eoselectivity of the reaction, but influences the regiochemistry as in the cycloaddition of 25 with 1,3-dimethyl-1,3-butadiene (Schemes 6.10 and 6.12). These results have been applied [24b-d] to the synthesis of azasugars (Scheme 6.14). 

Note that the regiochemistry of the cycloaddition (11) combines the most electrophilie... 

Such a stepwise reaction would not be expected to change the regiochemistry of cycloaddition, but it could lead to loss of stereospecificity if the zwitterionic intermediate has a long enough lifetime. In most reactions where only carbon-carbon bonds are being formed, the D-A reaction remains stereospecific. 

Two issues are of essential for predicting the structure of 1,3-DCA products (1) What is the regiochemistry and (2) What is the stereochemistry Many specific examples demonstrate that 1,3-dipolar cycloaddition is a stereospecific syn addition with respect to the dipolarophile, as expected for a concerted process. 

Dipolar cycloaddition of C60 with nitrile oxides was modeled at the B3LYP/6-31G(d,p)//AMl level, and its mechanism and regiochemistry were investigated. Theoretically, the reaction can proceed by four types of additions, viz., closed [6,6], open [5,6], closed [5,6], and open [6,6] additions. Analysis of... 

The [3 + 2]-cycloaddition reactions of allenes with 1,3-dipoles are useful for the construction of a variety of five-membered heterocycles with a high degree of regio- and stereochemical control [67]. Generally, the dipolar cycloaddition reactions are concerted and synchronous processes with a relatively early transition state. The stereoselectivities and regiochemistries are accounted for by the FMO theory The reaction pathway is favored when maximal HOMO-LUMO overlap is achieved. 

The regiochemistry of nickel mediated cycloadditions of substituted norbomadienes has been investigated in detail. The regioselectivity, exo/endo selectivity and site selectivity seem to depend strongly on the substituents on both diene and dienophile. Tetracya-noethene, for example, reacted with 2-acetyloxymethyl substituted norbomadiene on the distal side331. 

Vollhardt and colleagues338b studied the regiochemistry in these cycloaddition reactions. When the a,cu-diynes had large substituents at both termini, the reaction with W-phenylsulfonylindole did not afford any adduct due to steric hindrance. When smaller substituents were present, the cycloaddition proceeded in such a way that the larger substituent was distant from the phenylsulfonamide moiety, as illustrated for the reaction of 585 with 586 (equation 168). Anti 587 and syn 588 were obtained in a 61 39 ratio. 

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